tbuckley/cabot-search huggingface dataset:
Cytoplasmic YAP1‐mediated ESCRT‐III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer
Authors: Yan Guo, Yuqing Cui, Yangyang Li, Xiaoying Jin, Dandan Wang, Mengxia Lei, Fengzhi Chen, Yali Liu, Jinwen Xu, Guanyu Yao, Guangchun Zeng, Xuesong Chen
Journal: Cancer Communications (2023)

Abstract Background Nuclear Yes1‐associated transcriptional regulator (YAP1) promotes tumor progression. However, the function of cytoplasmic YAP1 in breast cancer cells and its impact on the survival of breast cancer patients remain unclear. Our research aimed to explore the biological function of cytoplasmic YAP1 in breast cancer cells and the possibility of cytoplasmic YAP1 as a predictive marker of breast cancer survival. Methods We constructed cell mutant models, including NLS‐YAP1 5SA (nuclear localized), YAP1 S94A (incapable of binding to the TEA domain transcription factor family) and YAP1 S127D (cytoplasmic localized), and used Cell Counting Kit‐8 (CCK‐8) assays, 5‐ethynyl‐2’‐deoxyuridine (EdU) incorporation assays, and Western blotting (WB) analysis to detect cell proliferation and apoptosis. The specific mechanism of cytoplasmic YAP1‐mediated endosomal sorting complexes required for transport III (ESCRT‐III) assembly was studied by co‐immunoprecipitation, immunofluorescence staining, and WB analysis. Epigallocatechin gallate (EGCG) was used to simulate YAP1 retention in the cytoplasm in in vitro and in vivo experiments to study the function of cytoplasmic YAP1. YAP1 binding to NEDD4‐like E3 ubiquitin protein ligase (NEDD4L) was identified using mass spectrometry and was verified in vitro. Breast tissue microarrays were used to analyze the relationship between cytoplasmic YAP1 expression and the survival of breast cancer patients. Results YAP1 was mainly expressed in the cytoplasm in breast cancer cells. Cytoplasmic YAP1 promoted autophagic death of breast cancer cells. Cytoplasmic YAP1 bound to the ESCRT‐III complex subunits charged multivesicular body protein 2B (CHMP2B) and vacuolar protein sorting 4 homolog B (VPS4B), promoting assembly of CHMP2B‐VPS4B and activating autophagosome formation. EGCG retained YAP1 in the cytoplasm, promoting the assembly of CHMP2B‐VPS4B to promote autophagic death of breast cancer cells. YAP1 bound to NEDD4L, and NEDD4L mediated ubiquitination and degradation of YAP1. Breast tissue microarrays revealed that high levels of cytoplasmic YAP1 were beneficial to the survival of breast cancer patients. Conclusions Cytoplasmic YAP1 mediated autophagic death of breast cancer cells by promoting assembly of the ESCRT‐III complex; furthermore, we established a new breast cancer survival prediction model based on cytoplasmic YAP1 expression.
Timely surgical fixation confers beneficial outcomes in patients’ concomitant flail chest with mild-to-moderate traumatic brain injury: a trauma quality improvement project analysis – a cohort study
Authors: Chien-An Liao, Ling-Wei Kuo, Jen-Fu Huang, Chih-Yuan Fu, Szu-An Chen, Yu-San Tee, Chi-Hsun Hsieh, Chien-Hung Liao, Chi-Tung Cheng, Tai-Horng Young, Chih-Po Hsu
Journal: International Journal of Surgery (2023)

Traumatic flail chest results in respiratory distress and prolonged hospital stay. Timely surgical fixation of the flail chest reduces respiratory complications, decreases ventilator dependence, and shortens hospital stays. Concomitant head injury is not unusual in these patients and can postpone surgical timing due to the need to monitor the status of intracranial injuries. Reducing pulmonary sequelae also assists in the recovery from traumatic brain injury and improves outcomes. No previous evidence supports that early rib fixation can improve the outcome of patients with concomitant flail chest and traumatic brain injury.Can early rib fixation improve the outcome of patients with concomitant flail chest and traumatic brain injury?Adult patients with blunt injuries from the Trauma Quality Improvement Project between 2017 and 2019 were eligible for inclusion. Patients were divided into two treatment groups: operative and nonoperative. Inverse probability treatment weighting was used to identify the predictors of mortality and adverse hospital events.Patients in the operative group had a higher intubation rate [odds ratio (OR), 2.336; 95% CI, 1.644-3.318; p <0.001), a longer length of stay (coefficient β , 4.664; SE, 0.789; p <0.001), longer ventilator days (coefficient β , 2.020; SE, 0.528; p <0.001), and lower mortality rate (OR], 0.247; 95% CI, 0.135-0.454; p <0.001).Timely rib fixation can improve the mortality rate of patients with flail chest and a concomitant mild-to-moderate head injury.
Sharing of Individual Patient-Level Data by Trialists of Randomized Clinical Trials of Pharmacological Treatments for COVID-19
Authors: Laura C. Esmail, Philipp Kapp, Rouba Assi, Julie Wood, Gabriela Regan, Philippe Ravaud, Isabelle Boutron
Journal: JAMA (2023)

This study describes access to individual patient-level data from randomized clinical trials during the COVID-19 pandemic to determine whether the intent to share what was reported in the registry, publication, or preprint was consistent with actual data access.
Weight loss during neoadjuvant therapy and short-term outcomes after esophagectomy: a retrospective cohort study
Authors: Yuki Hirano, Takaaki Konishi, Hidehiro Kaneko, Hidetaka Itoh, Satoru Matsuda, Hirofumi Kawakubo, Kazuaki Uda, Hiroki Matsui, Kiyohide Fushimi, Hiroyuki Daiko, Osamu Itano, Hideo Yasunaga, Yuko Kitagawa
Journal: International Journal of Surgery (2023)

Neoadjuvant therapy (NAT) has become common worldwide for resectable advanced esophageal cancer and frequently involves weight loss. Although failure to rescue (death after major complications) is known as an emerging surgical quality measure, little is known about the impact of weight loss during NAT on failure to rescue. This retrospective study aimed to investigate the association of weight loss during NAT and short-term outcomes, including failure to rescue after esophagectomy.Patients who underwent esophagectomy after NAT between July 2010 and March 2019 were identified from a Japanese nationwide inpatient database. Based on quartiles of percent weight change during NAT, patients were grouped into four categories of gain, stable, small loss, and loss (>4.5%). The primary outcomes were failure to rescue and in-hospital mortality. The secondary outcomes were major complications, respiratory complications, anastomotic leakage, and total hospitalization costs. Multivariable regression analyses were used to compare outcomes between the groups, adjusting for potential confounders, including baseline BMI.Among 15 159 eligible patients, in-hospital mortality and failure to rescue occurred in 302 (2.0%) and 302/5698 (5.3%) patients, respectively. Weight loss (>4.5%) compared to gain was associated with increased failure to rescue and in-hospital mortality [odds ratios 1.55 (95% CI: 1.10-2.20) and 1.53 (1.10-2.12), respectively]. Weight loss was also associated with increased total hospitalizations costs, but not with major complications, respiratory complications, and anastomotic leakage. In subgroup analyses, regardless of baseline BMI, weight loss (>4.8% in nonunderweight or >3.1% in underweight) was a risk factor for failure to rescue and in-hospital mortality.Weight loss during NAT was associated with failure to rescue and in-hospital mortality after esophagectomy, independent of baseline BMI. This emphasizes the importance of weight loss measurement during NAT to assess the risk for a subsequent esophagectomy.
Errors in the Figure
Authors: Michael Brouner, Jamey Hammock, Harish Doppalapudi, Tinsley Harrison
Journal: JAMA Internal Medicine (2023)

Zhilei Shan, MD, PhD; Fenglei Wang, PhD; Yanping Li, MD, PhD; Megu Y. Baden, MD, PhD; Shilpa N. Bhupathiraju, PhD; Dong D. Wang, MD, ScD; Qi Sun, MD, ScD; Kathryn M. Rexrode, MD, MPH; Eric B. Rimm, ScD; Lu Qi, MD, PhD; Fred K. Tabung, PhD; Edward L. Giovannucci, PhD; Walter C. Willett, MD, DrPH; JoAnn E. Manson, MD, DrPH; Qibin Qi, PhD; Frank B. Hu, MD, PhD
A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities
Authors: Michael McNicholas, Antonella De Cola, Zahedeh Bashardanesh, Amelia Foss, Cameron B. Lloyd, Steven Hébert, Damien Faury, Augusto Faria Andrade, Nada Jabado, Claudia L. Kleinman, Manav Pathania
Journal: Cancer Discovery (2023)

Abstract Pediatric high-grade gliomas (pHGG) are lethal, incurable brain tumors frequently driven by clonal mutations in histone genes. They often harbor a range of additional genetic alterations that correlate with different ages, anatomic locations, and tumor subtypes. We developed models representing 16 pHGG subtypes driven by different combinations of alterations targeted to specific brain regions. Tumors developed with varying latencies and cell lines derived from these models engrafted in syngeneic, immunocompetent mice with high penetrance. Targeted drug screening revealed unexpected selective vulnerabilities—H3.3G34R/PDGFRAC235Y to FGFR inhibition, H3.3K27M/PDGFRAWT to PDGFRA inhibition, and H3.3K27M/PDGFRAWT and H3.3K27M/PPM1DΔC/PIK3CAE545K to combined inhibition of MEK and PIK3CA. Moreover, H3.3K27M tumors with PIK3CA, NF1, and FGFR1 mutations were more invasive and harbored distinct additional phenotypes, such as exophytic spread, cranial nerve invasion, and spinal dissemination. Collectively, these models reveal that different partner alterations produce distinct effects on pHGG cellular composition, latency, invasiveness, and treatment sensitivity. Significance: Histone-mutant pediatric gliomas are a highly heterogeneous tumor entity. Different histone mutations correlate with different ages of onset, survival outcomes, brain regions, and partner alterations. We have developed models of histone-mutant gliomas that reflect this anatomic and genetic heterogeneity and provide evidence of subtype-specific biology and therapeutic targeting. See related commentary by Lubanszky and Hawkins, p. 1516. This article is highlighted in the In This Issue feature, p. 1501
Lithium in Drinking Water—A Novel Environmental Risk Factor for Autism Spectrum Disorder?
Authors: David C. Bellinger
Journal: JAMA Pediatrics (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Epigenetic regulation of HBV-specific tumor-infiltrating T cells in HBV-related HCC
Authors: Maojun You, Yanan Gao, Junliang Fu, Runze Xie, Zhenyu Zhu, Zhixian Hong, Lingzhan Meng, Shunda Du, Junliang Liu, Fu-Sheng Wang, Pengyuan Yang, Liang Chen
Journal: Hepatology (2023)

Background and Aims: HBV shapes the T-cell immune responses in HBV-related HCC. T cells can be recruited to the nidus, but limited T cells participate specifically in response to the HBV-related tumor microenvironment and HBV antigens. How epigenomic programs regulate T-cell compartments in virus-specific immune processes is unclear. Approach and Results: We developed Ti-ATAC-seq. 2 to map the T-cell receptor repertoire, epigenomic, and transcriptomic landscape of αβ T cells at both the bulk-cell and single-cell levels in 54 patients with HCC. We deeply investigated HBV-specific T cells and HBV-related T-cell subsets that specifically responded to HBV antigens and the HBV + tumor microenvironment, respectively, characterizing their T-cell receptor clonality and specificity and performing epigenomic profiling. A shared program comprising NFKB1/2-, Proto-Oncogene, NF-KB Sub unit, NFATC2-, and NR4A1-associated unique T-cell receptor-downstream core epigenomic and transcriptomic regulome commonly regulated the differentiation of HBV-specific regulatory T-cell (Treg) cells and CD8 + exhausted T cells; this program was also selectively enriched in the HBV-related Treg-CTLA4 and CD8-exhausted T cell-thymocyte selection associated high mobility subsets and drove greater clonal expansion in HBV-related Treg-CTLA4 subset. Overall, 54% of the effector and memory HBV-specific T cells are governed by transcription factor motifs of activator protein 1, NFE2, and BACH1/2, which have been reported to be associated with prolonged patient relapse-free survival. Moreover, HBV-related tumor-infiltrating Tregs correlated with both increased viral titer and poor prognosis in patients. Conclusions: This study provides insight into the cellular and molecular basis of the epigenomic programs that regulate the differentiation and generation of HBV-related T cells from viral infection and HBV + HCC unique immune exhaustion.
Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction
Authors: In-Young Jung, Robert L. Bartoszek, Andrew J. Rech, Sierra M. Collins, Soon-Keat Ooi, Erik F. Williams, Caitlin R. Hopkins, Vivek Narayan, Naomi B. Haas, Noelle V. Frey, Elizabeth O. Hexner, Donald L. Siegel, Gabriela Plesa, David L. Porter, Adrian Cantu, John K. Everett, Sonia Guedan, Shelley L. Berger, Frederic D. Bushman, Friederike Herbst, Joseph A. Fraietta
Journal: Cancer Discovery (2023)

Abstract Chimeric antigen receptor (CAR) T cell therapy has shown promise in treating hematologic cancers, but resistance is common and efficacy is limited in solid tumors. We found that CAR T cells autonomously propagate epigenetically programmed type I interferon signaling through chronic stimulation, which hampers antitumor function. EGR2 transcriptional regulator knockout not only blocks this type I interferon–mediated inhibitory program but also independently expands early memory CAR T cells with improved efficacy against liquid and solid tumors. The protective effect of EGR2 deletion in CAR T cells against chronic antigen-induced exhaustion can be overridden by interferon-β exposure, suggesting that EGR2 ablation suppresses dysfunction by inhibiting type I interferon signaling. Finally, a refined EGR2 gene signature is a biomarker for type I interferon–associated CAR T cell failure and shorter patient survival. These findings connect prolonged CAR T cell activation with deleterious immunoinflammatory signaling and point to an EGR2–type I interferon axis as a therapeutically amenable biological system. Significance: To improve CAR T cell therapy outcomes, modulating molecular determinants of CAR T cell–intrinsic resistance is crucial. Editing the gene encoding the EGR2 transcriptional regulator renders CAR T cells impervious to type I interferon pathway–induced dysfunction and improves memory differentiation, thereby addressing major barriers to progress for this emerging class of cancer immunotherapies. This article is highlighted in the In This Issue feature, p. 1501
Use of Sepsis Clinical Prediction Models to Improve Patient Care
Authors: Murtaza Mogri, Richard W. Grant, Vincent X. Liu
Journal: JAMA Internal Medicine (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
PB2316: EFFICACY AND SAFETY OF ELTROMBOPAG IN PEDIATRIC PATIENTS WITH PRIMARY IMMUNE THROMBOCYTOPENIA AND ITS EFFECT ON CELLULAR IMMUNE FUNCTION
Authors: 吴. 吴
Journal: HemaSphere (2022)

Background: eltrobopag is the only TPO-RA approved by the US FDA for the treatment of ITP in children, and foreign prospective multicenter randomized controlled clinical studies have found that atropopa has a good efficacy in the treatment of chronic ITP in children, and some children still maintain the efficacy after stopping the drug, but there are few reports on the application of atropopa in children with persistent/chronic ITP in China. The clinical data of the Treatment of Persistent/Chronic Pediatric ITP in the Second Affiliated Hospital of Anhui Medical University are retrospectively analyzed to evaluate the efficacy and safety of eltrobopag in the treatment of chronic/persistent ITP in children, and to explore the relevant factors that may affect the efficacy of Erlopapa in children, in order to better guide the clinical application of eltrobopag. Aims: To evaluate the efficacy and safety of eltrobopag in children with persistent /chronic ITP and to explore its effect on cellular immune function. Methods: The clinical characteristics of 28 pediatric persistent or chronic ITP patients who received eltrombopag from October 2019 to June 2021 were retrospectively analyzed. Results: 1、Efficacy: in total,20 patients (71.4%) achieved overall response, 12 (42.8%) achieved complete response, and 8 (28.5%) achieved partial response. And the clinical bleeding scores were significantly decreased after treatment (P < 0.05). In children with ITP who had a hematologic response, the median onset time was 14 d. 2、Safety: Eltrombopag was well tolerated, the common adverse events included elevated transaminase (5 cases) and serum bilirubin (1 case); None of the 28 children experienced serious adverse drug reactions during the treatment period. 3、 Platelet responses were not different irrespective of age, sex, disease duration, and bone marrow megakaryocyte count levels (P > 0.05). 4. Effects of eltrombopag on cellular immune function: there were no differences in the percentages of Treg cells， B lymphocytes, Th1, and Th2 cells between before and after treatment。But the group with higher pretreatment levels of Treg cells had better hematologic responses than the group with low levels of Treg cells (P < 0.05). Image:Summary/Conclusion: Eltrombopag is safe and effective in pediatric patients with primary ITP ，It can effectively reduce the bleeding risk of children with persistent / chronic ITP and improve the quality of life of children with ITP，and the level of Treg cells in children may be a predictor of eltrombopag response rate.
Seeking neuroprotection in multiple sclerosis: an ongoing challenge
Authors: Jack P. Antel, Timothy E. Kennedy, Tanja Kuhlmann
Journal: Journal of Clinical Investigation (2023)

Multiple sclerosis (MS) is an autoimmune disease of the CNS, featuring inflammation and demyelination with variable recovery. In this issue of the JCI, Kapell, Fazio, and authors address the potential for targeting neuron-oligodendrocyte potassium shuttling at the nodes of Ranvier as a neuroprotective strategy during inflammatory demyelination of the CNS in experimental MS. Their extensive and impressive study could serve as a template for defining the physiologic properties of a putative protective pathway. The authors examined MS features in existent disease models, investigated the impact of pharmacologic intervention, and evaluated its status in tissues from patients with MS. We await future studies that will tackle the challenge of translating these findings into a clinical therapy.
Conceptualising the commercial determinants of suicide: broadening the lens on suicide and self-harm prevention
Authors: May C I van Schalkwyk, Jeff Collin, Michael Eddleston, Mark Petticrew, Melissa Pearson, Lisa Schölin, Nason Maani, Flemming Konradsen, David Gunnell, Duleeka Knipe
Journal: The Lancet Psychiatry (2023)
LRH-1 induces hepatoprotective nonessential amino acids in response to acute liver injury
Authors: Kevin C. Klatt, Elizabeth J. Petviashvili, David D. Moore
Journal: Journal of Clinical Investigation (2023)

Acute hepatic injury is observed in response to various stressors, including trauma, ingestion of hepatic toxins, and hepatitis. Investigations to date have focused on extrinsic and intrinsic signals required for hepatocytes to proliferate and regenerate the liver in response to injury, though there is a more limited understanding of induced stress responses promoting hepatocyte survival upon acute injury. In this issue of the JCI, Sun and colleagues detail a mechanism by which local activation of the nuclear receptor liver receptor homolog-1 (LRH-1; NR5A2) directly induces de novo asparagine synthesis and expression of asparagine synthetase (ASNS) in response to injury and show that this response restrains hepatic damage. This work opens up several avenues for inquiry, including the potential for asparagine supplementation to ameliorate acute hepatic injury.
Glutamate shall not pass: a mechanistic role for astrocytic O-GlcNAc transferase in stress and depression
Authors: Sam E.J. Paton, Caroline Menard
Journal: Journal of Clinical Investigation (2023)

Major depressive disorder, characterized by aberrant glutamatergic signaling in the prefrontal cortex (PFC), is a leading cause of disability worldwide. Depression is highly comorbid with metabolic disorders, but a mechanistic link is elusive. In this issue of the JCI, Fan and coauthors report that elevated posttranslational modification with the glucose metabolite N-acetylglucosamine (GlcNAc) by O-GlcNAc transferase (OGT) contributed to stress-induced establishment of depression-like behaviors in mice. This effect was specific to medial PFC (mPFC) astrocytes, with glutamate transporter-1 (GLT-1) identified as an OGT target. Specifically, O-GlcNAcylation of GLT-1 resulted in diminished glutamate clearance from excitatory synapses. Further, astrocytic OGT knockdown restored stress-induced deficits in glutamatergic signaling, promoting resilience. These findings provide a mechanistic link between metabolism and depression and have relevance for antidepressant targets.